Local anesthesia is a pain control method most used in dentistry, one of the most feared procedures of dental practice, probably due to the perception of pain during needle insertion. Fear and anxiety associated with the anticipation of painful sensations represent barriers to dental care.
One of the most common techniques used to avoid or minimize discomfort induced by the application of local anesthesia involves the use of topical anesthetics prior to needle puncture. Despite the relative effectiveness obtained with this technique, the fear of pain and needles are still common, probably because the topical anesthetic does not guarantee full effectiveness. Because of this, well-defined and safe anesthetic techniques, associated with the use of effective anesthetics, may provide a more adequate pain control during dental care, especially in pediatric patients.
The effectiveness of topical anesthetics depends on some factors such as the anesthetic agent used, the topical anesthetic application time, the contact time, the application site and type of mucosa, the pharmaceutical topical anesthetic form (adhesive solution or mouthwash, gel or other forms), the diameter of the needle used, and the depth of penetration of the needle, among others.
The use of topical local anesthesia before the injection of local infiltrative anesthesia is the main method used to minimize the pain of needle insertion, so the anesthetic should have a faster onset of action and have sufficient length and penetration to be effective as a topical anesthetic.
Topical anesthetics were developed to relieve pain, especially in dental procedures. However, new uses for these anesthetics were added, such as sprays for use in the mouth and throat, gels used for pain relief in conditions like appearance of the teeth, gels and mouthwashes for use in canker sores, mouth irritation and gums, gels and ointments for use in the region of the lips and oral solutions for local anesthesia of the larynx, pharynx and esophagus to be ingested prior to performing certain medical tests and procedures.
Also in dentistry, more recently, specific products in the form of waxes or masses have been developed to prevent, and in some cases, treat lesions caused by braces or bands of tethers.
Because of its rapid onset of action (30 seconds on average), acceptable taste and low systemic absorption, the gel with 20% benzocaine has been a widely used anesthetic agent, especially in pediatric dentistry. Despite these advantages, adverse reactions such as methemoglobinemia have been documented after topical benzocaine.
Lidocaine is not associated with methemoglobinemia, a condition which involves iron ion oxidation of ferrous state (Fe2+) to the ferric state (Fe3+), making the hemoglobin molecule incapable of carrying oxygen.
For this reason, the products developed for use in pediatric dentistry must take into account, mainly the toxic potential of the anesthetics used, to avoid the types of unwanted reactions that may occur during or after the dental procedure.
The main local anesthetics currently used belong to two groups of substances, amides and esters. The group of amides is the most used, with its main anesthetics: lidocaine (Xylocaine), bupivacaine, levobupivacaine, prilocaine, mepivacaine, and ropivacaine.
In the group of the main anesthetic esters are tetracaine, benzocaine, procaine (Novocaine) and propoxycaine. There is also the articaine, the sole representative of the amide group with a thiophene grouping, discovered more recently.
Also in relation to the characterization of the anesthetics currently used in dentistry, tertiary amines with hydrophilic and lipophilic properties stand out for being a less toxic alternative, being more effective and having low allergenic potential than ester-type anesthetics, although they have been synthesized for a longer time in the 1940s. Ropivacaine and levobupivacaine are safer alternatives to bupivacaine because it has lower systemic toxicity.
One of the problems presented by local anesthetics is that they can cause mild to severe reactions. The most frequent reactions to these anesthetics are vaso-vagal, which can cause sweating, malaise, tachycardia, fainting and results to a neuro-vegetative reaction derived from fear, anxiety or panic.
The toxic reactions result from the use of excessive amount of anesthetic or accidental introduction in the blood vessels of the numbed region; these constitute the majority of the reactions described, with no allergic mechanism.
Allergic reactions, although rare (about 1%) may be more severe and intense. The most common is allergic contact dermatitis which resulting from a topical application on skin and mucous membranes of the anesthetic in the form of creams, ointments, gels and solutions. Allergic reactions to topical anesthetics can be prevented through clinical evaluation and analysis of the previous episode, then performing a skin test with the alternative anesthetic. Generally, lidocaine is used as an allergy test because of its widespread use and low incidence of reactions. The use of topical anesthetics is contraindicated for children under 2 years of age, especially in large areas (except for cases where there is strict professional supervision) in people with previous reports of hypersensitivity to benzocaine or other topical anesthetic of the ester type and in patients with severe burn at the site to be treated.
There are cases where the risks and benefits should be assessed in order to decide whether or not to use these drugs. The FDA has new restrictions on the use of certain anesthetics. Benzocaine is one it was found that it could lead to a problem called hemoglobinemia, which is a serious and potentially fatal adverse reaction. The target hemoglobinemia may occur minutes or hours after the application of benzocaine, even in the first application; it is most common in children under 2 years of age or younger.
In search of an ideal topical anesthetic, research results have shown the effectiveness of EMLA® (AstraZeneca™), formed by the eutectic mixture of lidocaine and prilocaine, both at 2.5%. Although this is not an anesthetic injection indicated for dental use, topical application in the oral mucosa has allowed the execution of procedures such as periodontal instrumentation, dentistry and, in some cases, extraction of deciduous and pulp therapies in pediatric dentistry and even biopsies.
The EMLA® also reduces the discomfort of intraligamentary injections and punctures in the palatal mucosa. A review of the literature from 1985 has shown that although the EMLA® provides analgesia in the most effective oral mucosa than topical anesthetics commercially available for dental use also has significant adverse effects: the main ones are bitter taste, burning sensation in the mucosa; and in some cases, it can cause allergic dermatitis, contact urticaria, and intense inflammatory reaction; and the high cost.
Although traditional topical anesthetics actually reduce the discomfort associated with needle insertion, the pain still felt and reported by patients undergoing this procedure is relevant, and this deserves the attention of researchers for the development of new and better products that enable an adequate and effective topical anesthesia.
Of all the regions of the oral cavity, the palatal mucosa is known for difficulty achieving adequate topical anesthesia. Obtaining effective topical anesthesia in the palatal mucosa is more difficult due to increased keratinization of this site and the presence of a dense connective tissue strongly adhered to the bone, making it difficult to stretch during the injection of the anesthetic solution. As the palatal mucosa is one of the most sensitive and painful areas of the oral cavity, the evaluation model of topical anesthesia on this site is the biggest challenge that a topical anesthetic can be submitted to. Thus, a topical anesthetic able to eliminate or significantly reduce pain during needle puncture and injection of an anesthetic solution in this region will be a breakthrough for dentistry.
The literature reports the low efficacy of topical anesthetics on the palate, as exemplified by the topical anesthetic action of 20% benzocaine gel compared to placebo, for some authors is effective, while for others it does not show the divergence on in reducing patient discomfort to the puncture site on the palate. This demonstrates the need for greater investment or more research with a focus to solve or alleviate the pain during the dental procedure.
Positive results can arise from the discovery of new anesthetics associated between them, or by the use of more concentrated dosage forms of drugs currently used, but with absorption/action restricted to the site of interest.
Disorders like ulcers or varied etiology of lesions on the lips and oral mucous membranes or in the upper digestive tract, such as the throat and esophagus, are also causing considerable pain and suffering. For the lips and oral areas, a wide variety of anesthetic products are available that are added or not in the other classes of drugs, commercial or manipulated, formulated from what is pharmaceutically known as “Orabase”, a kind of gel more palatable and a suitable constitution to use in the mouth or on the lips on repeated applications.
Current topical anesthetics intended for the oral region, in most cases, including those made in orabase, regardless of active anesthetic principles, are presented in the form of mouthwashes and solutions for application in the form of spray or gels and ointments, which generally are efficient as to its purpose as a topical anesthetic, but its use has the following drawbacks:                form of spreading—for the application of gels and ointments, using a spatula is needed or the tip of the finger or another suitable device, which does not always guarantee full hygiene;        need for removal of excess ointment or gel for subsequent insertion needle for the application of injectable local anesthetic—which is typically carried out using cotton, which possibly may leave residues in the mouth of the patient, which is uncomfortable;        uncertainty of doses and the difficulty of small areas affect limitation—the application in the form of mouthwashes and sprays practically precludes the use of precise doses and application reduces the site of interest.        
Gels and ointments, although they may be applied on a greater control area, do not allow the use of accurate doses and even bring, on the other hand, the drawback of partially anesthetized area and inconveniently anesthetize other nearby areas, especially the cheek and tongue, due to the direct contact with the topical anesthetic or because of the spread of this to the surrounding areas, and can also generate what is called gustatory anesthesia; do not allow clear identification of the site that will later be numbed by the use of injectable anesthetics; do not allow the use of higher concentrations of anesthetic due to the ineffectiveness in controlling the dose used and the fact that topical anesthetics can cause serious side effects and adverse reactions.
For new forms of topical anesthetics to be considered, a development in this area should have characteristics such as precise control of doses; The greater speed and intensity of anesthetic action due to the possibility of using more concentrated forms; Efficient adhesion even in wet areas; And when necessary, a longer-lasting action of the topical anesthetic in controlled release function. They will constitute as a major breakthrough in relation to topical anesthesia of the mouth and upper digestive tract. It is also related to medical practices, dental or investments made by the patient.
Topical anesthetics are among the first pharmaceutical forms formulated with local anesthetics and are still being used.
The document WO 2010/008601 A1 reports a topical anesthetic solution with a drug delivery system for fast location anesthetic action. The drug delivery system described herein includes a topical anesthetic agent, an alkane diol, a fatty acid (or the corresponding alcohol) or ester with a lower melting temperature than 40° C., and a volatile solvent (such as an alcohol short chain with silicone).
Among the more recent patent documents, the published US patent application, US 2012/0083452A1 relates to liquefied compositions of local anesthetics for topical application that includes different anesthetics, Szeto-Schiller peptides, and a carrier for penetration such as lecithin, and may further contain a vasoconstrictor and tyrosine. More advanced controlled release systems may be used in the solutions.
The document EP 0,767,669 provides topical anesthetic pharmaceutical compositions in the form of an ointment or cream, which have one or more topical anesthetic agents, a polar lipid, a triacylglycerol and optionally water. The controlled release system of the invention is a nanoparticle encapsulated in a microparticle sensitive to moisture. The nanoparticles have a diameter of about 0.01 microns-to 10 microns, having a solid hydrophobic core and a positively charged bioadhesive/mucoadhesive surface. The invention also provides their use in oral hygiene products (such as toothpaste) and for the treatment and/or prevention of the periodontal disease, since the nanoparticles could also be effective for the release of biologically active substances into the periodontal pocket.
The use of the pharmaceutical gel has recently been the classic tool used to obtain a certain adhesion of the carrier vehicle for anesthetics for topical application to the site. Among the documents of general anesthetics use, the published US patent application US 2007/0280972 A1 foresees the use of an adhesive gel drug delivery system for the dermal tissue and may include medicine, solvent, and gelling agents. When applied on the skin, the compound can form a gel layer that solidifies after the evaporation of at least a part of the volatile gel system. Furthermore, the solidified gel layer could be removed even by washing with designated solvents.
Among the documents which relate to the use of topical anesthetics also for dental use is BR 0406117 document, which describes a gel for treatment of mouth ulcers with cicatrizing and anesthetic effect, especially for patients using orthodontic appliances and have thrush; Natrosol is composed of a gelling agent, glycolic extract of propolis, dexamethasone acetate, lidocaine, nipagin, nipazol and distilled water.
The published Brazilian document BR 0704542 A2 discloses a pharmaceutical composition for topical anesthetic gel directed to use in dental procedures, comprising a pharmaceutically effective amount of at least one anesthetic and a gelling agent. The invention would allow for greater penetration of the anesthetic through a stable viscosity that keeps the drug for a longer duration and at a higher concentration at the site of action; thus, increasing the duration of the anesthesia and reducing their toxicity.
To alleviate the pain for a longer time, the international publication WO 2002/000195A1 describes various anesthetic compositions in gel form for the injured mucosa due to abrasions, ulcerations, trauma or incisions. The compositions of this invention are particularly suitable for application to the mucosa of the oral cavity and nose as well.
The published US application US 2012/0034307A1 also involves the formulation of an aqueous gel and a method for inducing anesthesia. This US document describes a composition containing water, an anesthetic (such as lidocaine hydrochloride), the viscoelastic polymer hydroxypropylmethylcellulose, and a tonicity modifier.
In recent years, the encapsulation of anesthetic agents into liposomes has been described and studied, this includes the document CN 102406609, which relates to the use of lidocaine HCl liposome encapsulated in polymers. The encapsulation rate of the polymeric liposome was between 60 and 85%, while the diameter of the grain that liposome would lie between 60 and 180 nm. The lidocaine hydrochloride may be applied directly to the skin surface, mucous membrane, or be in the form of a gel or an ointment.
Alternatively, the anesthetic can be incorporated into nanoparticles. The uses of polymeric nanoparticles are provided in the International publication WO 2008/113144A1, which describes nanoparticulate anesthetic compositions for topical use wherein at least one anesthetic agent would be encapsulated in polymeric nanoparticles suspended in the hydrogel and could be applied topically, both on the skin and mucosa.
Topical anesthetic preparations in gel form can also be embedded or attached to inert carriers, occlusive or not. International Publication WO 2001/002477A1 relates to the use of a compound containing a self-adhesive pre-formed layer of gel for topical application, containing less than 10% of a mixture of polysaccharides consisting of gellan gum; xanthan gum is a polysaccharide mannosylated (this selected from a galactomannan or glucomannan derivative, or mixtures thereof). Still possess about 30% to 99.5% water, wherein the compound comprises less than 10% total polysaccharide. The product would be suitable for topical use, is easy to use, is discreet, and would be in accordance with the contours of the surface target when applied.
The international publication WO 2002/89849A1 relates to a pharmaceutical anesthetic composition for topical administration. The composition comprises, besides a therapeutically effective amount of the anesthetic, a vehicle that does not trigger liposomal release thereof, consisting mainly of a monohydric alcohol, a penetration enhancer and a polymer (which can be a hydrophilic polymer, hydrophobic or a combination of both). This material, gel-like in consistency, would allow a rapid onset of anesthesia and the penetration of the active agent into the skin.
The published American application US 2010/0092546A1 discloses compositions and methods for the treatment of chronic wounds, also including diabetic ulcers. The material would allow the transdermal administration of an agent that increases the activity of HIF-1 modulator to the wound, such as deferoxamine, deferiprone, deferasirox, etc. The topical dosage forms, which contain the lotion, would modulate agents and biodegradable gel ethylcellulose, and polyvinylpyrrolidone, and transdermal patches.
Also among the documents that report the use of shapes with adhesive properties, EP 649650B1 relates to a bioadhesive pharmaceutical composition in tablet form for controlled release of several local active principles through the buccal cavity, or systemically through a mucous membrane, but does not include topical anesthetics. Xanthan is a polymeric component of the composition mentioned.
In dental use, information is provided by the published American application US 2011/0315151 A1 regarding an adhesive molding for protection and relief of pain in the oral mucosa caused by orthodontic appliances. The compound can be made from orthodontic wax, polymers or other flexible biocompatible materials in the main form of strips. They can be applied directly to the braces to protect the lining of direct contact. The product can have different colors, flavors and display different topical anesthetics or drugs in their composition.
The use of biodegradable polymers as a matrix for controlled release of anesthetic is described in the International Publication WO 9936071 A1, which provides the use of a controlled release system consisting of 30 to 99.0% of a biodegradable polymer matrix, comprising biodegradable polymers such as albumin, collagen and polycaprolactone and polyalkylcyanoacrylates, non-biodegradable, among others, but does not include xanthan-containing embedded anesthetics.
The publication EP 1,132,080 also provides the use of a biodegradable polymeric matrix for incorporation of local anesthetics to control the persistent pain of various etiologies.
Meanwhile, the use of biodegradable microspheres is disclosed in the U.S. Pat. No. 6,214,387. The microspheres would be formed by a biodegradable polymer. Among the possible ones are the polyanhydrides, PLGA-poly (lactic acid-co-glycolic acid)—and polyorthoesters containing a catalyst, but no xanthan. Prolonged release of the anesthetic would be obtained by incorporating a glucocorticoid within the polymer matrix, or by co-administration with glucocorticoid microspheres. The type of anesthetic and the quantity would be selected based on the known pharmaceutical properties of different compounds.
Finally, the anesthetic efficiency and stability of topical anesthetic drugs in pharmaceutical preparations are closely related to the pH of the preparation. The relative proportion of the free base and the charged soluble or water-soluble cationic form of topical anesthetic affects the absorption and activity and depends on the solution pH. The water-soluble and fat-soluble balance should be carefully observed according to the place of use of the adhesive, as the tissues have pH variables; in the mouth, for example, the pH varies between 6.8 and 7.4, which causes the free base to be released and this enters the nerve that is rich in lipids.
The published application US 2008/0242731 A1 comprises the liquefied topical anesthetic formulations, its uses and methods for their preparations. It particularly refers to a combination of anesthetic substances, solubilizing agents, and viscosifying agents, resulting in a buffered topical anesthetic composition that has a pH, viscosity, and properties suitable for the reduction of pain associated with injury, trauma or any other source of pain sensitivity. Xanthan is among the cited viscosifying agents.
Xanthan is a non-toxic water-soluble fiber of microbial origin, produced by bacteria of the genus Xanthomonas. 
Xanthan is released by the Ministry of Health as a food additive in Brazil since 1965 and by the FDA since 1969 and is currently widely used in pharmaceuticals.
The xanthan gum produced by Xanthomonas arboricola pv. pruni is a biopolymer that allows more progress in the field of development of new formulations of topical anesthetics adhesives, differentiated by their chemical composition and, in some cases, molar mass and high thermal resistance.
Various mechanical and dissolution properties may be obtained by using different xanthans, chemically modified or not, or by association with specific substances that allow the use of different methods for obtaining anesthetics adhesives.
Although xanthan is an extracellular biopolymer already established, it continues to demand research worldwide both in prospecting for new pathovars and producing strains and in search of xanthan with different features for new applications.
Research has been carried out in Brazil since the 80s and still, today, it is generating several patents and publications on xanthan production, including: BR8805325B1, BR406309-0 and WO 2006047845, BR0701765-0A2; BR1004194-0 and all documents cited on the use of X. campestris pv. campestris, except BR 8805325 B1 using X. campestris pv. manhiotis, and published application WO 2006047845A1 BR0406309-0 and Xanthomonas arboricola pv. using pruni, other species for the production of xanthan.
International Publication WO 2006047845A1 still stands out as the only document that has a different composition of the xanthan presence of rhamnose among its monomeric sugars, the pruni xanthan. This difference and the chemical modifications that can be made in their structure can profoundly transform the polymer and therefore its characteristics, enabling its use in various fields, bringing a new range of uses. To certify the safety of pruni Xanthan, various studies and tests were conducted that showed the absence of genotoxic and cytotoxic effects.
The chemical and physical properties of xanthan, especially the viscosity and stability with respect to pH variations, ion concentration, and temperature, make this polymer widely used in pharmaceutical, food, exploitation of oil, and as a thickener and stabilizing suspensions and emulsions.
Among the above-mentioned characteristics that stand out for the functionality of the proposed use in the said international document are the viscosity and pH stability over a wide range that is maintained almost unchanged from pH 2 to pH 12, which covers all dissociation constants (pK) of topical anesthetics or sites most commonly used mepivacaine 7.6; lidocaine and prilocaine 7.9; bupivacaine 8:1; 8.5 tetracaine and procaine 9:1.
A good anesthetic agent should have a low systemic toxicity, not be irritating to the tissues and not cause permanent damage to the nervous structures. The time for onset of local anesthesia should be as short as possible and the duration of action is sufficient for the surgical procedure, with reversible action.
Recent research is looking for ways to control the release of drugs to ensure an increase in the duration of the effect(s) of anesthetic(s) that are associated with decreased toxicity. Among these forms to obtain topical anesthetic formulations using carriers different in solubility and release of the anesthetic drug, but with high biocompatibility (with the oral mucosa) have been the specific focus of studies leading to the present application.
The use of polymers or biopolymers materials that allow the controlled release (such as xanthan with or without other biopolymers) and knowledge of the primary active ingredient (in this case the anesthetic) are fundamental to the development of new compositions. This will allow obtaining new pharmaceutical forms of topical anesthetics for the mouth and upper digestive tract, including the esophagus, such as wires, tapes, strips and adhesive films.
The possibility of using previous and exact doses depending on the applied area, the adhesiveness of the product in question, containing the anesthetic and added or not to drugs with other actions, which have their controlled release at the mucosal surface, will minimize or eliminate the occurrence of overdose and unwanted action in adjacent areas and prolong the effect of analgesia, which is short on topical anesthetics available today.
It would be interesting if the technique could have stickers, BAT type film or tape, consisting of biocompatible and biodegradable biopolymer matrix where the main constituent of support or matrix, which are incorporated in local anesthetics for topical use, is xanthan.